The integrating theme of the research proposed in this Program Project Grant (PPG) application is that depression must be disaggregated into its constituent parts to understand why it is a prognostic risk for major adverse cardiac events and/or all cause mortality (MACE/ACM) in patients after an Acute Coronary Syndrome (ACS). The emergence of genetics and genomics research over the past decade has created great excitement in its promise for increasing our ability to prevent and more powerfully treat the major chronic diseases such as CHD. In particular, genetic studies have enormous potential to improve our understanding of how depression increases risk for MACE/ACM, or to determine if there is a common genetic vulnerability for both of these complex phenotypes. This potential remains to be fully realized, in part because of our current inability to identify reliable, enduring, and conceptually distinct depression components or intermediary phenotypes that mark patients at risk. We propose in this PPG that studying depression intermediary phenotypes will advance the field by: a) improving prognostic risk prediction; b) identifying specific targets for candidate genes underlying the risk conferred by depression; and c) identifying targets for treatments designed to ultimately improve cardiac and mortality outcome. It is also essential to gain an understanding of the mechanisms through which the depression intermediary phenotypes act. We propose to test if the Melancholic Depression and Incident Depression, two intermediary phenotypes with a distinct etiology and course, are uniquely predictive of 1-year MACE/ACM (Project 1), and if promising behavioral mechanisms (Project 2) and biological mechanisms (Project 3) mediate/confound the association between these depression intermediary phenotypes and MACE/ACM. In Project 1 we will enroll 1,400 ACS patients, phenotype their depression (i.e., Melancholic, Incident, or Other), and follow them for major adverse cardiovascular outcomes and all-cause mortality for one year; in Project 2 we will enroll 1,134 patients from Project 1 and electronically monitor their aspirin, clopidogrel, beta blocker and statin medications for up to one year; we will also assess a number of other promising behavioral mechanisms. In Project 3 we will enroll 1,260 ACS patients from Project 1 and assess their inflammatory levels and platelet aggregation at hospitalization, when medications are known to be ingested, and one month later, when non-adherence may affect these biological mechanisms. This proposed PPG will address the NHLBI Strategic Plan, Goal #2, by identifying those depression phenotypes and mechanisms that place ACS patients at excess cardiac and mortality risk. Doing so will identify potentially more successful and personalized intervention strategies, and accelerate our ability to discover the genes implicated in depression's risk for cardiac disease and death.